Since the mid-seventies, the prevalence of obesity among adults has increased sharply. Data from two National Health and Nutrition Examination Surveys show that among adults 20-74 years of age the prevalence of obesity increased from 15.0% (in the 1976-1980 survey) to 32.9% (in the 2003-2004 survey).
Obesity and certain conditions associated with obesity, such as diabetes, are often treated by encouraging patients to lose weight by reducing their caloric intake or by increasing their level of physical activity. However, for many individuals, maintaining a reduced calorie diet and an exercise regime is difficult, and often such treatment results in poor patient compliance. For many individuals weight loss drugs can serve as a successful treatment in conjunction with, or as an alternative to diet and exercise. However, certain currently available weight loss drugs, which include orlistat [Davidson, M. H. et al., JAMA, 281: 235-42 (1999)], effect weight loss by preventing lipid absorption by the body and, as a result, are limited by gastrointestinal side effects.
Recently, cannabinoid 1 (CB-1) receptor modulators, such as rimonabant, which is sold as ACOMPLIA in many countries, have been found to effect weight loss by targeting receptors in the brain linked to appetite. Since CB-1 receptor modulators effect weight loss through a different mechanism than that of orlistat, CB-1 receptor modulators are not limited by the same gastrointestinal side effects.
One promising weight loss drug is CB-1 receptor inverse agonist, taranabant, which is further described in WO2003/077847, which is incorporated herein by reference in its entirety. Taranabant, however, is insoluble in aqueous solution, making processing and manufacturing an issue. Therefore, there exists a need for stable, solid pharmaceutical formulations, and processes for making such formulations, that include water insoluble drugs, such as taranabant.
Additionally, it is quite common that effective treatment of an obese individual may not only include treating the obesity but also treating any conditions associated with obesity that the individual may also be suffering from. Conditions associated with obesity include, but are not limited to diabetes; hypertension; elevated plasma insulin concentrations; insulin resistance; dyslipidemia; hyperlipidemia; endometrial, breast, prostate, kidney and colon cancer; osteoarthritis; respiratory complications, such as obstructive sleep apnea; gallstones; atherosclerosis; heart disease; abnormal heart rhythms; and heart arrhythmias (Kopelman, P. G., Nature, 404: 635-643 (2000)). Therefore, there is also a need for stable pharmaceutical formulations, and processes of making such formulations, that can include water insoluble drugs, such as taranabant, and other therapeutic agents. Certain combinations of taranabant and other therapeutic agents are described in WO 2006/119260, which is incorporated by reference in its entirety.
However, processing and manufacturing single dosage forms that contain a water insoluble therapeutic agent, such as taranabant, and an additional therapeutic agent, such as a water soluble therapeutic agent, is difficult. Generally, water insoluble therapeutic agents are formulated into liquid dosage forms, such as liquid-filled capsules, using lipids. Adding a water soluble therapeutic agent to such a formulation is problematic due to the fact that the water soluble drug may have solubility or stability issues when introduced into the liquid lipid formulation. Thus, there is not only a need for stable pharmaceutical formulations that can include water insoluble drugs, such as taranabant, and other therapeutic agents, but there is a need for stable, solid pharmaceutical formulations and processes of making such formulations that can include water insoluble drugs, such as taranabant, and water soluble therapeutic agents that can be formed into solid, oral single fixed dosage forms. Also there is a need for such pharmaceutical formulations to improve the bioavailability of one or both of the therapeutic agents or at least result in equivalent bioavailability of one or both of the therapeutic agents compared to separate administration of each of the therapeutic agents.